1. Field of the Invention
This invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (neotame) using novel oxazolidinone derivatives. This method of producing neotame is an alternative to the conventional synthetic route for producing neotame which uses aspartame as a starting material.
2. Related Background Art
N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (neotame) is a high potency dipeptide sweetener (about 8000× sweeter than sucrose) that has the formula

Neotame may be synthesized using a variety of synthetic methods. The chemical synthesis of neotame is disclosed in U.S. Pat. No. 5,480,668, U.S. Pat. No. 5,510,508, U.S. Pat. No. 5,728,862, U.S. Pat. No. 6,077,962 and WO 00/15656, the disclosure of each of which is incorporated by reference herein.
U.S. Pat. Nos. 5,510,508 and 5,728,862 describe the synthesis of neotame by hydrogenation of a mixture of aspartame and 3,3-dimethylbutyraldehyde with a catalyst such as Pd on carbon. This synthesis is represented by the following equation.

International Patent Publication No. WO 00/15656 describes the formation of neotame by hydrogenation of a mixture of 3,3-dimethylbutyraldehyde and Z-aspartame (N-benzyloxycarbonyl-L-α-aspartyl-L-phenylalanine-1-methyl ester) in a methanolic solvent. U.S. Pat. No. 6,077,962 describes the synthesis of neotame using a peptide coupling method of an activated derivative of N-(3,3-dimethylbutyl)-L-aspartic acid and L-phenylalanine or L-phenylalanine methyl ester.
The literature teaches regioselective methods for the formation of α-aspartyl peptide bonds, as opposed to β-aspartyl peptide bonds, in the synthesis of aspartame. One of these methods comprises the cyclocondensation of carbonyl compounds with N-protected aspartic acid as described in Chinese Patent CN 11748844 A. The resulting oxazolidinone derivative, having the structure
wherein PG is a protecting group, R1 is H or R2, R2 is CX3 and X is Cl, Br or F, has the α-aspartyl carbonyl as an ester and the β-aspartyl carbonyl as a carboxylic acid. Thus, only the α-aspartyl carbonyl is activated for peptide bond formation. The nitrogen protecting groups included Z, Boc, formyl and acetyl groups.
Other examples in the literature teach regioselective methods for the formation of α-aspartyl peptide bonds, as opposed to β-aspartyl peptide bonds. Such methods comprise the cyclocondensation of carbonyl compounds with aspartic acid without nitrogen protection. In these cases, the nitrogen of the oxazolidinone derivative having the structure
is an amine and not part of an amide, as was the case where nitrogen was protected.
The treatment of neohexyl-L-aspartic acid with carbonyl compounds to form oxazolidinone derivatives useful in the selective preparation of neotame without the formation of the beta isomer is not described in the above-described art.
It would be desirable, however, to develop more efficient and cost-effective methods of preparing high purity neotame from readily available or readily obtainable materials.